Abstract From biomarker studies, animal models and human histology, the occurrence of heart failure (HF) is increasingly recognized as an inflammatory process. Carefully-designed experiments in animal models have identified the importance of innate and adaptive immune cells in the development and progression of HF. But whether innate and adaptive immune cells in humans are also the active authors of cardiovascular health and pathology remains an hypothesis largely untested. HF is a complex syndrome characterized by the inability of the heart to adequately meet metabolic demands due to reduced cardiac output, elevated filling pressures, or both. Although there is some overlap, the two major types include (1) HF with preserved ejection fraction (HFpEF), typically associated with hypertension (HTN), diabetes (DM), and obesity, and (2) HF with reduced ejection fraction (HFrEF), often associated with atherosclerosis and myocardial infarction (MI). In the setting of cardiomyocyte injury or cell death, the development of HF is likely to depend on the type and intensity of immune-cell activation. Largely on the basis of experiments in animal models (section 3a), we hypothesize that high densities of pro-inflammatory immune cells are risk factors for the incidence of HF, especially HFrEF; that high densities of pro-fibrotic immune cells are also risk factors for the incidence of HF, especially HFpEF; and that high-densities of regulatory immune cells that control inflammation and fibrosis reduce the risk of both HFpEF and HFrEF. With the advent of technological advances, peripheral blood mononuclear cells, collected in 1998-1999 in the Cardiovascular Health Study and in 2000-2002 in the Multi-Ethnic Study of Atherosclerosis and cryopreserved since then at -140oC, provide a unique opportunity to conduct, in humans, a longitudinal study of the densities of innate and adaptive immune cells as risk factors for the incidence of HF, both HFrEF and HFpEF. The proposed case-cohort study adds HF to on-going MI case-cohort study and will include more than 800 HF events plus a random sample from each cohort for a total of about 4200 participants from the 2 studies. Using flow cytometry on the cryopreserved cells from baseline, we will assay 17 immune-cell subsets. The primary aim is to evaluate their association prospectively with HF events and its two main types, HFpEF and HFrEF. The secondary aim includes analyses of immune-cell subsets as risk factors for the incidence of other outcomes such as DM, HTN, and atrial fibrillation. This revised application includes preliminary data from the ongoing MI study, comparisons of assays done on MESA specimens five years apart, and a new replication effort, which brings the total number of HF events to more than 1000. The proposed study is well powered. Although treatments targeting the immune system have improved the therapeutic options for several cancers, the development and use of immune-related therapies to prevent HF await further discovery about the potential role of immune cells in HF.